A variety of medical conditions have been treated by introducing an insertable medical device having a coating for release of a biologically active material. For example, various types of biologically active material-coated medical devices, such as stents, have been proposed for localized delivery of the biologically active material to a body lumen. See, e.g., U.S. Pat. No. 6,099,562 to Ding et al. However, it has been noted that, with existing coated medical devices, the release profile of a biologically active material may not be uniform along the entire length of the medical device.
For example, even if a biologically active material having a pharmacological effect is delivered to a body tissue, such effect may not result if the concentration of the biologically active material in the body tissue is below a certain concentration. Such concentration is referred to as the minimum effective concentration (Cmin) of the biologically active material in the body tissue. Each biologically active material has different Cmin. Cmin of a biologically active material also varies depending on the type of body tissue to which it is delivered. On the other hand, a biologically active material becomes toxic if its concentration is higher than a certain concentration. Such concentration is referred to as the maximum effective concentration Cmax. In addition, it is insufficient that the mean concentration of the biologically active material delivered through out the body tissue to be treated is greater than Cmin and smaller than Cmax. The concentration of the biologically active material at each and every area throughout the body tissue to be treated should be equal to or greater than Cmin but equal to or smaller than Cmax of the biologically active material. For instance, when a coated stent comprised of struts, such as the stent shown in FIG. 1, is used as a medical device for delivering a hydrophobic biologically active material, concentrations of the biologically active material may significantly differ between the regions of the tissue adjacent to the struts and the regions of the tissue farther from the struts. See Hwang et al., http://www.circulationaha.org (accepted in April 2001). Even if the mean concentration of the biologically active material in the tissue surrounding the stent is above Cmin of the biologically active material and at or under Cmax, the concentrations at certain regions of the tissue to be treated, which are farther from the struts, may not reach Cmin. Also, if the amount of the biologically active material in the coating is increased to achieve a concentration higher than Cmin at all regions of the tissue to be treated, then the concentrations at regions of the tissue adjacent to the struts may exceed the toxic levels, as explained below using the figures.
In FIG. 1, the coated stent 10 is placed in a blood vessel 15 having a vessel wall 12 to be treated. This vessel wall is surrounded by tissue 12a. The biologically active material coated on struts 13 of the stent 10 is released into the vessel wall 12 to be treated. FIG. 2 is a cross sectional view along line A of the stent 10 in FIG. 1. FIG. 2 also shows the concentration levels of the biologically active material in each area surrounding the struts 13 at a certain time after the insertion of the stent into the vessel 15. The area adjacent to the struts, i.e., the area between the struts 13 and line 16, has a concentration level at or below Cmax, which is just below the toxic level. The farther from the struts 13 the tissue to be treated is located, the lower the concentration of biologically active material delivered to the tissue becomes. However, the area between line 18 and line 19 has the concentration level at or higher than Cmin. A concentration of the biologically active material in the area outside line 19 is below Cmin.
Also, FIGS. 2A and 2B clearly show that there are gaps between each strut 13 wherein the vessel wall to be treated does not receive sufficient biologically active material to have Cmin. The areas within line 19, i.e., having concentrations above Cmin, may be increased in size to include more area of the vessel wall to be treated 12, if the amount of the biologically active material on the struts 13 is increased. However, by doing so, the concentration of the biologically active material in the area adjacent to the struts 13 may exceed the toxic level. Accordingly, there is a need for a medical device comprising a plurality of struts that can achieve the biologically active material concentration that is above Cmin and below toxic levels throughout the tissue.
However, exposure to a medical device which is implanted or inserted into the body of a patient can cause the body tissue to exhibit adverse physiological reactions. For instance, the insertion or implantation of certain catheters or stents can lead to the formation of emboli or clots in blood vessels. Other adverse reactions to vascular intervention include endothelial and smooth muscle cell proliferation which can lead to hyperplasia, restenosis, i.e., the re-occlusion of the artery, occlusion of blood vessels, platelet aggregation, and calcification. Restenosis is caused by an accumulation of extracellular matrix containing collagen and proteoglycans in association with smooth muscle cells which is found in both the atheroma and the arterial hyperplastic lesion after balloon injury or clinical angioplasty. Treatment of restenosis often involves a second angioplasty or bypass surgery. The drawbacks of such treatment, including the risk of repeat restenosis, are obvious.
When considering treatment using biologically active material eluting stents, there are several considerations. Firstly, implantation of a drug eluting stent requires precise placement of the stent so that the lesion covered by the stent includes a sufficient margin beyond the angiographically identified lesion boundaries. Hence, even with very careful placement of the stent, it is possible to miss or undertreat the lesion. Secondly, even if a lesion appears to be fully covered by a biologically active material coated stent, balloon injury caused during implantation may extend well beyond the ends of the stent. In the case where such injury can be visualized by angiography, an additional stent may be placed to cover this injury. However, implantation of a second stent may cause further injury in a similar fashion to placement of the first stent. Thirdly, even if there is no evidence of angiographic injury, there may be a zone of biological injury that is well beyond the ends of the stent.
Other problems with the current technology, in particular radioactive stents, is that restenosis may still occur at the parts of the surface of the body lumen that are in contact with the ends of a stent. Closure or constriction of the vessels commonly occurs when the vascular cells proliferate around the ends of the stent. This is known as the “candy-wrapper effect”, also known as edge restenosis or edge effect. Albiero et al., 2000, J. Invas. Cardiol. 12(8):416-421; Latchem et al., 2000, Catheter Cardiovasc Interv. 51(4):422-429; Kim et al., 2001, J. Am. Coll. Cardiol. 37(4):1026-1030. A schematic diagram describing this effect is show in FIG. 25. FIG. 25 shows a cross section of a body lumen with a stent implant where restenosis occurred at the opposing ends of the stent. The surface 10 of a body lumen 30 at the ends of the implanted stent 40 is surrounded by hyperproliferating tissues 20. This appearance is similar to a candy with a wrapper and thus the name “candy-wrapper effect”. A cause for some types of hyperplasia is that when a body lumen is treated with radiation, the radioactive source is usually targeted towards the center of the stent where the original lesion was situated. In an effort to minimize extraneous radiation to healthy vessel tissue, radiation is targeted towards the center. Hence, restenosis may still occur at the edge of the stent due to a lower dosage of radiation at the ends. The underlying mechanism for this effect is that the radiation dosage at the ends is at a level such that it stimulates cell growth as opposed to stopping it. Clearly, there remains a great need for therapies directed to the prevention and treatment of restenosis and related disorders.
The edge-effect also can occur with non-radioactive stents. With existing coated medical devices, generally, the coating of the biologically active material is uniformly applied along the entire length of the device or surface of the device. For example, conventional coated stents are coated uniformly along the entire length of the surface of the device. The biologically active material-concentration-profile in the body lumen along the length of the coated surface may be in the shape of a bell-curve, wherein the amount of the biologically active material released at the middle of the surface causes a greater tissue concentration than the amount of the biologically active material released at the ends of the coated surface. This uneven concentration-profile in the body lumen along the length of the coated surface may lead to the application of an inadequate or sub-optimal dosage of the biologically active material to the body tissue located at the ends of the coated surface. It is possible that such uneven local concentration of the biologically active material in the wall of the body lumen along the length of the coated surface of the medical device may lead to undesired effects. For example, in the case of a biologically active material-coated stent used to prevent or treat restenosis, if the amount of biologically active material delivered to the tissue located at the ends of the stent is sub-optimal, it is possible that restenosis may occur in such tissue.
The biologically active material dosage at the tissue located at the ends of the coated surface of the medical device can be increased if the concentration or amount of the biologically active material is increased along the entire length of the surface. However, by increasing the concentration or amount of biologically active material released along the entire surface, the dosage delivered to tissue located at the middle of the surface may be too great or even at toxic levels.
Thus, there is a need for a medical device that allows precise placement of the stent with respect to the lesion, a more uniform concentration-profile for biologically active material along the entire length of a coated surface of a medical device, and provide a means for therapeutic concentration of biologically active material at and beyond the physical ends of an implanted stent. This invention avoids the possibility of undesired effects and in particular, preventing intimal hyperplasia and smooth muscle cell proliferation which cause stenosis or restenosis of the body lumen caused by an uneven biologically active material concentration-profile.
Moreover, medical devices wherein a biologically active material is uniformly coated on the entire outer surface of the medical devices that is exposed to body tissue are generally used to deliver such biologically active material to specific parts of such body tissue. For instance, such devices are used to treat lesions in body lumen. However, because the entire outer surface of the device contains the biologically active material, this biologically active material will be delivered to healthy body tissue in addition to the lesion. Treatment of healthy tissue with the biologically active material is not only unnecessary but maybe harmful. Accordingly, there is a need for a medical device that can realize an asymmetry release profile of biologically active material to deliver such material to only a limited region of the body tissue that requires the biologically active material.
Citation of references hereinabove shall not be construed as an admission that such references are prior art to the present invention.